Funded Projects

NOFO Title: Optimization of Non-addictive Therapies [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-19-010
Summary:

Neuropathic pain is characterized by neuronal hyperexcitability and spontaneous activity, properties associated with activity of hyperpolarization-activated, cyclic nucleotide-regulated (HCN1-4) channels, the source of the pacemaker current, Ih. Inhibition of HCN1-mediated Ih elicits marked antihyperalgesia in multiple animal models of neuropathic pain, including models for direct nerve injury and chemotherapy-induced peripheral neuropathy, and does so with little or no disruption to either normal pain processing or baseline behaviors and activities. The overall objective is to develop a peripherally restricted HCN1 inverse-agonist as a therapeutic for neuropathic pain. Researchers have generated a novel small molecule that combines an antihyperalgesic HCN1 inhibitor with a motif that controls distribution and membrane presentation and is a potential non-opioid antihyperalgesic treatment for peripheral neuropathic pain.

NOFO Title: HEAL Initiative: HEALthy Brain and Child Development Study (HEALthy BCD) (R34 Clinical Trial Not Allowed)
NOFO Number: RFA-DA-19-036
Summary:

This study will determine the feasibility of a multifaceted approach to recruitment of normal and high-risk pregnant women and their children. Three inter-related tasks will support this comprehensive feasibility study. First, an interdisciplinary summit will occur early in the study focused on how best to mitigate risks and maximize benefits to children and families recruited in a future cohort. Second, the feasibility of a multi-faceted recruitment strategy will be assessed. Third, select pregnancy and birth assessments will be collected from recruited participants in this feasibility study while leveraging data across early childhood from existing resources, to inform Phase II study planning. This Phase I of the FL-DECADE study will provide valuable planning and feasibility data to be used for the national efforts to build a large, prospective cohort.

NOFO Title: Advanced Laboratories for Accelerating the Reach and Impact of Treatments for Youth and Adults with Mental Illness (ALACRITY) Research Centers (P50 Clinical Trial Optional)
NOFO Number: PAR-18-701

NOFO Title: PHS 2018-02 Omnibus Solicitation of the NIH, CDC, and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44] Clinical Trial Not Allowed)
NOFO Number: PA-18-574
Summary:

There is a compelling need to develop a front line, non-opioid-based acute pain management strategy for outpatient oral surgical procedures. LaunchPad Medical has developed Tetranite® (TN), a novel bone regenerative mineral-organic self-setting adhesive biomaterial. TN has been extensively studied in vivo in a canine jaw model and shown to be effective and well-tolerated. In this project, researchers will demonstrate that drug-loaded TN can be a novel route to providing localized and time release pain medication following wisdom tooth extraction by determining the release profile of various pain medications from TN at different concentrations. The ability to release pain therapeutics in a controlled fashion and directly at the site of injury offers improved pain control following oral surgical procedures without exposing the patient to opioids. This novel approach to pain management can be extended to more invasive orthopedic procedures such as joint replacement, spinal fusions or reconstructive trauma surgery. In Phase II the team will conduct an in vivo study to assess efficacy of medicated TN to address post-operative pain following wisdom tooth odontectomy, optimize incorporation and release of medications in TN formulations, develop cGMP manufacturing process for the compounded product, and ultimately conduct clinical trials for bone void filler using medicated TN.

NOFO Title: HEAL Initiative: America’s Startups and Small Businesses Build Technologies to Stop the Opioid Crisis (R43/R44 - Clinical Trial Optional)
NOFO Number: RFA-DA-19-019
Summary:

The increase in prevalence of cancer coupled with an increase in the cancer survival rates due to chemotherapy regimens is transforming cancer pain into a large, unmet medical problem. Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially dose-limiting side effect of many cancer drug treatment regimens and is caused in part by alterations in ion channels; blocking or depleting Cav3.2 channels in dorsal root ganglion (DRG) neurons should thus mediate analgesic effects. This proposal aims to develop and test potent, orally available, and selective Cav3.2 channel antagonists, building on the structure of a medicinal plant product—betulinic acid (BA)—that has been identified to be Cav3.2-selective and antinociceptive in CIPN. Such compounds could reduce the reliance on opioids in cancer patients.

NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional)
NOFO Number: RFA-DA-19-002
Summary:

Chronic pain affects an estimated 100 million Americans, or one third of the U.S. population, and it is the primary reason Americans are on disability. Although many treatments are available for pain, the most potent class of analgesics relies on opioid analogs, whose limitations and well-known adverse effects have contributed to the present opioid crisis. New pharmacotherapies for pain management are sorely needed. MTX1604, a synthetic endomorphin analog, has emerged as a highly effective analgesic that exhibits reduced reward potential and respiratory suppression, and a robust duration of efficacy in a variety of validated animal models of acute, neuropathic, inflammatory, post-operative, and visceral pain. This project will generate additional preclinical characterization data of MTX1604 and advance clinical development toward FDA approval. If successful, this medication development project could offer patients a novel non-addictive, potent, and safe analgesic and thus have a direct impact on the opioid crisis.

NOFO Title: HEAL Initiative: Sleep and Circadian-Dependent Mechanisms Contributing to Opiate Use Disorder (OUD) and Response to Medication Assisted Treatment (MAT) (R01 - Clinical Trial Not Allowed)
NOFO Number: RFA-HL-19-028
Summary:

Among the most common symptoms experienced by individuals suffering with opioid use disorder (OUD) are severe sleep and circadian disruptions. The relationship between opioid dependence and sleep and circadian systems is not well understood. A circadian-dependent mechanism has been shown to modulate fentanyl reward-related behaviors in the nucleus accumbens (NAc). The study team will use a combination of behavioral, slice electrophysiology, and molecular approaches to 1) investigate the role of the circadian transcription factor NPAS2 in medium spiny neurons with dopamine 1 (D1R-MSNs); 2) assess the impact of fentanyl on synaptic plasticity at D1R-MSNs and investigate whether NPAS2 mediates the potentiation of excitatory synapses at specific diurnal phases; 3) elucidate the cell-type-specific NPAS2-dependent transcriptional mechanisms of fentanyl-seeking and relapse behaviors; and 4) investigate whether NPAS2 rescue and buprenorphine medication-assisted treatment (MAT) improve fentanyl-induced sleep disturbances. This study will define the role for circadian-dependent transcriptional mechanisms and uncover the therapeutic potential of NPAS2 for opioid dependence and relapse.

NOFO Title: HEAL Initiative: Effectiveness Trials to Optimize, Implement, Scale, and Sustain the Collaborative Care Model for Individuals with Opioid Use Disorders and Mental Health Conditions (U01 Clinical Trial Required)
NOFO Number: RFA-MH-19-525
Summary:

This study will refine and test a collaborative care model for patients with opioid use disorder (OUD) and major depression, post-traumatic stress disorder, or an anxiety disorder in primary care. The primary aims of the study are: (1) prototype and test elements of the research team’s collaborative care models; (2) conduct a randomized study of three collaborative care conditions to determine which is most effective in improving outcomes for people with OUD and mental health conditions: Augmented Usual Care, Collaborative Care, or Collaborative Care + Social Worker; (3) measure clinician and organizational-level factors associated with implementation to increase success; (4) conduct a cost evaluation of each collaborative care model; and (5) work with smaller and rural practices to develop and test effective strategies to manage OUD. Successful completion of this study will provide evidence regarding the elements of integrated collaborative care required to maximize outcomes for individuals with OUD and psychiatric disorders.

NOFO Title: HEAL Initiative: HEALthy Brain and Child Development Study (HEALthy BCD) (Collaborative R34 Clinical Trial Not Allowed)
NOFO Number: RFA-DA-19-029
Summary:

A more than 5-fold increase in the incidence of neonatal abstinence syndrome has been reported since 2000. Preliminary studies show that prenatal opioid exposure is associated with increased risk of impaired neurodevelopment. Five institutions (Duke University, Arkansas Children’s Research Institute, Cincinnati Children’s Hospital, University of Illinois at Urbana–Champaign, and University of North Carolina at Chapel Hill) have formed a consortium to develop strategies for the Phase II HEALthy Brain and Child Development Study. Research teams will develop instruments and strategies (recruitment/retention protocols, assessment batteries, and novel tools); conduct pilot studies (fetal and postnatal imaging, advanced imaging harmonization and quality control, assessment administration, biosampling) to evaluate instruments; and analyze available data, including imaging, behavioral, cognitive, and maternal data from studies on early brain development, to guide the Phase II study design. Upon completion, the consortium aims to conduct the Phase II study.

NOFO Title: Blueprint Neurotherapeutics Network (BPN): Small Molecule Drug Discovery and Development for Disorders of the Nervous System (U44 Clinical Trial Optional)
NOFO Number: PAR-18-541
Summary:

We propose to develop a safe and effective nonopioid analgesic to treat neuropathic pain that targets an isoform of the voltage-gated sodium ion channel, NaV1.7. Voltage-gated sodium channels are involved in the transmission of nociceptive signals from their site of origin in the peripheral terminals of DRG neurons to the synaptic terminals in the dorsal horn. NaV1.7 is the most abundant tetrodotoxin-sensitive sodium channel in small diameter myelinated and unmyelinated afferents, where it has been shown to modulate excitability and set the threshold for action potentials. Development of systemic NaV1.7 inhibitors has been complicated by the challenge of achieving selectivity over other NaV isoforms expressed throughout the body. We have discovered a series of potent, state-independent NaV1.7 inhibitors that exhibit >1000-fold selectivity over other human isoforms. Work conducted under this program will support advancement of a lead candidate into clinical development as a therapeutic for neuropathic pain.

NOFO Title: Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)
NOFO Number: PA-18-591
Summary:

The goal of this proposal is to launch an innovative, multi-modal neuroimaging program that will investigate the longitudinal trajectory of the neurodevelopment of irritability across the preschool period. Differentiating clinically salient irritability from developmentally normative temperamental variation has proven to be a difficult task. This is made even more challenging during the preschool period, when irritability has hit its normative peak and measuring neurodevelopment is impeded by methodological constraints. This research will (1) identify specific biomarkers underlying preschool vulnerability for psychopathology by examining neural maturation in executive function as a predictor for clinical outcome; and (2) examine how the parenting environment moderates this vulnerability, with the overarching objective of identifying aberrant irritable trajectories as the foundation for future brain-based behavioral intervention. Primary analyses will (1) probe underlying executive function as a predictor of clinical outcome; and (2) examine parent-child neural synchrony as a predictor of executive function maturation.

NOFO Title: HEAL Initiative Limited Competition: Behavioral Research to Improve MAT: Ancillary Studies to Enhance Behavioral or Social Interventions to Improve Adherence to Medication Assisted Treatment for Opioid Use Disorders (R01 Clinical Trial Optional)
NOFO Number: RFA-AT-19-007
Summary:

Washington state used federal Opioid-STR funding to develop the Washington State Hub and Spoke Model (H&S), an integrated care model to expand access to OUD medications by incorporating primary care and substance use treatment programs, referral organizations, nurse care managers, and care navigators. Based on the initial success, Washington provided more funding and developed a second-generation, low-barrier H&S model, to place medication initiation sites in nontraditional settings, such as emergency departments, syringe exchanges, jails, and homeless shelters, and to have community partners offer OUD medication maintenance. The study will determine the implementation and effectiveness of the new H&S model, maintaining a hybrid effectiveness-implementation approach, and utilizing social network analysis to understand how H&S networks develop to serve the OUD population. The findings will demonstrate what makes the H&S model effective for increasing OUD medication treatment, improving outcomes for people with OUD, and reaching individuals who may not seek treatment.

NOFO Title: The National Drug Abuse Treatment Clinical Trials Network (UG1)
NOFO Number: RFA-DA-15-008
Summary:

According to SAMHSA’s 2017 National Survey on Drug Use and Health (NSDUH), 11.4 million persons in the U.S. report past-year opioid misuse; out of them, only 2.1 million individuals met criteria for an OUD. Very little is known about efficacious interventions for those who do not meet criteria for moderate/severe OUD (i.e., subthreshold OUD). The prevalence of subthreshold OUD in primary care settings is 5 percent to 10 percent, with higher rates (21 percent to 29 percent) among those receiving prescribed opioids. Although they are at high risk of developing moderate/severe OUD and/or dying from an overdose, little or no empirical evidence exists for pragmatic prevention interventions that can be adopted at integrated general medical settings. To study the efficacy of prevention interventions to arrest the progression from risky opioid use, researchers will test the efficacy of a STOP intervention in primary care settings. STOP adopts an early intervention approach, based on a collaborative care model to prevent progression to moderate/severe OUD, and consists of a practice-embedded nurse care manager who provides patient education and supports the primary care provider (PCP) in engaging, monitoring and guiding patients who have risky opioid use; brief advice delivered to patients by their PCP; and phone counseling of patients by behavioral health providers to motivate and support behavior change. Researchers will determine whether STOP reduces risky opioid use and examine the impact of STOP on progression to moderate/severe OUD, overdose risk behavior and overdose events in adults with risky use of illicit or prescription opioids.